Responses to endothelium-dependent agonists in subcutaneous arteries excised from hypercholesterolaemic men

Abstract

1. Vasomotor function of the vascular endothelium was examined in human subcutaneous arteries excised from 8 hypercholesterolaemic and 7 normolipidaemic subjects. 2. Left gluteal skin biopsies were performed under local anaesthesia. Subcutaneous arteries were isolated and two vessels from each subject mounted in separate myographs. A 20 ml fasting blood sample was taken at the time of the biopsy. 3. Hypercholesterolaemic subjects had either never been treated with lipid lowering therapy or therapy had been stopped at least two weeks before the study (n = 2). At the time of the study total plasma cholesterol levels (control: 4.6 ± 0.3 vs hypercholesterolaemic: 8.3 ± 0.6 mmol l-1: P < 0.01) were significantly elevated in hypercholesterolaemic subjects when compared with controls. 4. Full concentration-response curves to the vasoconstrictor noradrenaline and the vasodilators acetylcholine and substance P were constructed. A single point concentration-response to sodium nitroprusside (10 μM) was also obtained. Dilator responses were obtained in vessels pre-constricted with a submaximal concentration of noradrenaline. Vessels were then incubated for 30 min with either L- or D-arginine (10 μM) and the concentration-response curves to the three dilator agonists repeated in the presence of the amino acid. 5. Maximum relaxation responses to acetylcholine (control vs hypercholesterolaemic: 83.3 ± 6.1% vs 47.4 ± 13.5%; P < 0.05), but not to substance P or sodium nitroprusside, were dampened in the hypercholesterolaemic group when compared with controls. 6. Neither incubation with L-arginine nor D-arginine had any effect on maximum relaxation responses to acetylcholine in either the control group (pre L-arginine vs plus L-arginine: 83.3 ± 6.1 vs 82.3 ± 5.5%, pre D-arginine vs plus D-arginine: 98.9 ± 1.2 vs 98.2 ± 1.1%) or the hypercholesterolaemic group (pre L-arginine vs plus L-arginine: 47.4 ± 13.5 vs 55.3 ± 14.3%, pre D-arginine vs plus D-argenine: 43.3 ± 13.6 vs 65.4 ± 12.3%). 7. When results from the two study groups were pooled, the strongest predictor of maximum relaxation obtained to acetylcholine was apolipoprotein A(t) (r = 0.67; P = 0.001). 8. In conclusion, relaxation responses mediated by the endothelium-dependent agonist acetylcholine, but not by substance P, are impaired in hypercholesterolaemic patients. L-Arginine did not improve the impaired relaxation responses to acetylcholine. We suggest that impaired endothelium-dependent relaxation is specific to acetylcholine and not to an abnormal L-arginine-nitric oxide pathway in subcutaneous arteries excised from this study group.